TY - JOUR
T1 - Anandamide Hydrolysis Inhibition Reverses the Long-Term Behavioral and Gene Expression Alterations Induced by MK-801 in Male Rats
T2 - Differential CB1 and CB2 Receptor-Mediated Effects
AU - Bauminger, Hagar
AU - Zaidan, Hiba
AU - Akirav, Irit
AU - Gaisler-Salomon, Inna
N1 - Publisher Copyright:
© 2022 The Author(s) 2022.
PY - 2022/6/21
Y1 - 2022/6/21
N2 - NMDA receptor blockade in rodents is commonly used to induce schizophrenia-like behavioral abnormalities, including cognitive deficits and social dysfunction. Aberrant glutamate and GABA transmission, particularly in adolescence, is implicated in these behavioral abnormalities. The endocannabinoid system modulates glutamate and GABA transmission, but the impact of endocannabinoid modulation on cognitive and social dysfunction is unclear. Here, we asked whether late-adolescence administration of the anandamide hydrolysis inhibitor URB597 can reverse behavioral deficits induced by early-adolescence administration of the NMDA receptor blocker MK-801. In parallel, we assessed the impact of MK-801 and URB597 on mRNA expression of glutamate and GABA markers. We found that URB597 prevented MK-801-induced novel object recognition deficits and social interaction abnormalities in adult rats, and reversed glutamate and GABA aberrations in the prelimbic PFC. URB597-mediated reversal of MK-801-induced social interaction deficits was mediated by the CB1 receptor, whereas the reversal of cognitive deficits was mediated by the CB2 receptor. This was paralleled by the reversal of CB1 and CB2 receptor expression abnormalities in the basolateral amygdala and prelimbic PFC, respectively. Together, our findings show that interfering with NMDA receptor function in early adolescence has a lasting impact on phenotypes resembling the negative symptoms and cognitive deficits of schizophrenia and on glutamate and GABA marker expression in the PFC. Prevention of behavioral and molecular abnormalities by late-adolescence URB597 via CB1 and CB2 receptors suggests that endocannabinoid stimulation may have therapeutic potential in addressing treatment-resistant symptoms.
AB - NMDA receptor blockade in rodents is commonly used to induce schizophrenia-like behavioral abnormalities, including cognitive deficits and social dysfunction. Aberrant glutamate and GABA transmission, particularly in adolescence, is implicated in these behavioral abnormalities. The endocannabinoid system modulates glutamate and GABA transmission, but the impact of endocannabinoid modulation on cognitive and social dysfunction is unclear. Here, we asked whether late-adolescence administration of the anandamide hydrolysis inhibitor URB597 can reverse behavioral deficits induced by early-adolescence administration of the NMDA receptor blocker MK-801. In parallel, we assessed the impact of MK-801 and URB597 on mRNA expression of glutamate and GABA markers. We found that URB597 prevented MK-801-induced novel object recognition deficits and social interaction abnormalities in adult rats, and reversed glutamate and GABA aberrations in the prelimbic PFC. URB597-mediated reversal of MK-801-induced social interaction deficits was mediated by the CB1 receptor, whereas the reversal of cognitive deficits was mediated by the CB2 receptor. This was paralleled by the reversal of CB1 and CB2 receptor expression abnormalities in the basolateral amygdala and prelimbic PFC, respectively. Together, our findings show that interfering with NMDA receptor function in early adolescence has a lasting impact on phenotypes resembling the negative symptoms and cognitive deficits of schizophrenia and on glutamate and GABA marker expression in the PFC. Prevention of behavioral and molecular abnormalities by late-adolescence URB597 via CB1 and CB2 receptors suggests that endocannabinoid stimulation may have therapeutic potential in addressing treatment-resistant symptoms.
KW - CB1
KW - CB2
KW - NMDA receptor
KW - URB597
KW - animal model
KW - schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=85132454942&partnerID=8YFLogxK
U2 - 10.1093/schbul/sbab153
DO - 10.1093/schbul/sbab153
M3 - Article
C2 - 35092675
AN - SCOPUS:85132454942
SN - 0586-7614
VL - 48
SP - 795
EP - 803
JO - Schizophrenia Bulletin
JF - Schizophrenia Bulletin
IS - 4
ER -